Regulation of Notch signaling by dynamic changes in the precision of S3 cleavage of Notch-1
Regulation of Notch signaling by dynamic changes in the precision of S3 cleavage of Notch-1
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DOI：
10.1128/mcb.00863-07
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发表时间：
2008-01-01
影响因子：
5.3
通讯作者：
Takeda, Masatoshi
中科院分区：
文献类型：
--
作者：
Tagami, Shinji;Okochi, Masayasu;Takeda, Masatoshi
早老素依赖性γ-分泌酶的膜内蛋白水解产生Notch细胞内胞质结构域(NCID)和阿尔茨海默病相关的淀粉样蛋白-β。在这里，我们表明，在 Notch 信号传导后，由于 S3 切割位点的多样性，Notch-1 的胞内结构域被切割成两种不同类型的 NICD 物种。与 N 端规则一致，S3-V 裂解产生 N 末端具有 Val 的稳定 NICD，而 S3-S/S3-L 裂解产生 N 末端具有 Ser/Leu 的不稳定 NICD。此外，不稳定NICD的细胞内Notch信号传输比稳定NICD弱得多。重要的是，靶细胞内吞作用的程度影响两种类型 NICD 的相对生产比率，其变化与 Notch 信号传导平行。令人惊讶的是，Val -> Gly 和 Lys -> Arg 突变体产生了大量不稳定的 NICD 物种，据报道这些突变体会降低培养细胞中的 S3 裂解效率。因此，我们认为两种不同类型的 NICD 的存在表明了细胞内信号传导的一个新方面，并且 S3 切割精度的变化在从细胞外到细胞内 Notch 信号传导的转换过程中发挥着重要作用。
Intramembrane proteolysis by presenilin-dependent gamma-secretase produces the Notch intracellular cytoplasmic domain (NCID) and Alzheimer disease-associated amyloid-beta. Here, we show that upon Notch signaling the intracellular domain of Notch-1 is cleaved into two distinct types of NICD species due to diversity in the site of S3 cleavage. Consistent with the N-end rule, the S3-V cleavage produces stable NICD with Val at the N terminus, whereas the S3-S/S3-L cleavage generates unstable NICD with Ser/Leu at the N terminus. Moreover, intracellular Notch signal transmission with unstable NICDs is much weaker than that with stable NICD. Importantly, the extent of endocytosis in target cells affects the relative production ratio of the two types of NICD, which changes in parallel with Notch signaling. Surprisingly, substantial amounts of unstable NICD species are generated from the Val -> Gly and the Lys -> Arg mutants, which have been reported to decrease S3 cleavage efficiency in cultured cells. Thus, we suggest that the existence of two distinct types of NICD points to a novel aspect of the intracellular signaling and that changes in the precision of S3 cleavage play an important role in the process of conversion from extracellular to intracellular Notch signaling.